Key words
thromboembolisms - pregnancy - anticoagulation - low-molecular-weight heparins - oral
anticoagulants
Introduction
In comparison to non-pregnant women, pregnant women have a significantly increased
risk of venous thrombotic events (VTE), that is, deep and superficial venous thromboses
(“thrombophlebitis”) and consequent pulmonary artery embolisms. In the Western world,
these events represent a leading cause of morbidity and mortality in pregnant women
[1]. This means that VTEs are responsible for about 10 – 20% of all deaths within the
scope of pregnancy [1], [2], [3], [4], [5], [6], [7], [8], [9], [10].
The incidence of pregnancy-associated VTEs is indicated at approx. 0.12% [11], [12]; in comparison to non-pregnant women of the same age, pregnant women thus have per
se an approximately 4 – 5 times higher risk of VTE. This thrombotic risk which is
alone elevated by the pregnancy increases further if additional predispositional and
expositional risk factors for VTE are present in the pregnant woman. It should be
pointed out in this regard that due to demographic changes with a significantly increasing
maternal age at first pregnancy in recent decades – and thus a higher percentage of
“older” pregnant women – the risk of thrombotic and thromboembolic events in the entire
collective of pregnant women in industrial nations such as Germany is increasing further
[4], [9].
The increased risk of thrombosis begins with the start of pregnancy, persists during
pregnancy (or further increases throughout the course of the pregnancy) and reaches
its maximum in the postpartum period; after delivery, the risk of thrombosis decreases
over a period of approx. 6 weeks to the level prior to pregnancy. About 50% of pregnancy-associated
VTEs occur during pregnancy itself and 50% in the “critical period” within six weeks
after delivery [5]; thus the risk of postpartum thrombosis is about 5 times higher than during pregnancy
itself.
Prothrombotic Shifting of the Haemostatic Balance in Pregnancy
Prothrombotic Shifting of the Haemostatic Balance in Pregnancy
The physiological prothrombotic shift of the haemostatic balance in pregnancy is of
major significance for the significantly increased risk of thrombosis in pregnant
women in comparison to nonpregnant women. Procoagulatory factors increase (e.g. activities
of the plasmatic coagulation factors), while coagulation components which control
or curb the coagulation process significantly decrease; a good example of this is
the physiological decrease in protein S activity in pregnancy. In addition, there
is a modification of fibrinolysis, whereby the increase in plasminogen activator inhibitor
(PAI-1) in pregnancy has an antifibrinolytic effect and thus contributes to the prothrombotic
shift of the haemostatic balance. The latter is also reflected in an increase in the
activation markers of haemostasis (e.g. D-dimers, fibrin degradation products [FDP],
thrombin-antithrombin complex [TAT] and prothrombin fragment) [9], [13], [14], [15], [16], [17].
In late pregnancy, the plasma volume increases by up to 1600 ml compared to the starting
value [18]. This also contributes to venous stasis and an increased risk of coagulation in
connection with a decreased venous return flow due to the increasing pressure of the
gravid uterus on the vena cava.
Predispositional and Expositional Risk Factors
Predispositional and Expositional Risk Factors
Predispositional and expositional risk factors favour the development of VTEs in pregnancy
[19]; here, predisposition means the individual predisposition of the pregnant woman
to thrombotic events (intrinsic risk), while expositional risk factors are factors
which act on the pregnant woman externally which situationally increase the risk of
thrombosis (so-called “triggers”). Important risk factors for thrombotic events in
pregnant women are listed in [Table 1]. The most clinically relevant factors are discussed separately below.
Table 1 Important risk factors for VTEs in pregnancy.
|
Category
|
Risk factor
|
|
General risk factors
|
|
|
Previous and concomitant illnesses
|
-
Previous VTE (thrombosis, pulmonary embolism)
-
Previous thrombophlebitis
-
Chronic inflammatory diseases
-
Sickle cell anaemia
-
Heart diseases
-
Diabetes mellitus
-
Arterial hypertension
-
Nicotine use
|
|
Complications of pregnancy and delivery
|
|
|
Iatrogenic risk factors
|
|
|
Thrombophilia
|
See [Table 2]
|
Previous history of thrombotic events
Previous deep venous thromboses and pulmonary artery embolisms, particularly spontaneous
or hormonally triggered events – especially during administration of hormonal contraception
– are associated with a significantly increased risk of recurrence during pregnancy.
After spontaneous or hormonally triggered events, a risk of recurrence of approx.
10% during pregnancy can be assumed without adequate thrombosis prophylaxis and this
can be even considerably higher if there are other predispositional and expositional
risk factors [9], [20], [21], [22]. Previous superficial venous thromboses (thrombophlebitis), depending on severity,
are associated with a risk of VTE in pregnancy and the postpartum period which is
about 10 times higher. This risk can be reduced to approx. 2 – 3% with adequate secondary
prophylaxis.
Thrombophilia
Genetically determined thrombophilia
Genetically determined or acquired thrombophilia affects the VTE risk in pregnancy.
The corresponding relative and absolute risks for carriers of genetically determined
thrombophilic risk factors are compiled in [Table 2].
Table 2 Relative risk of VTE in pregnancy and absolute risk derived from this for women with
significant hereditary thrombophilic risk factors, depending on the family history
[23], [24], [25], [26], [27], [28], [29], [30].
|
Risk factor
|
Relative thrombosis risk
|
Absolute thrombosis risk in pregnancy and postpartum period
|
|
Unremarkable family history
|
Positive family history
|
|
* Risk increase and absolute thrombosis risk in inhibitor deficiencies depending on
the nature and degree of severity of the respective defect.
|
|
Factor V Leiden mutation
|
|
|
|
|
|
8.32
|
0.8 – 1.2%
|
3.1%
|
|
|
34.4
|
3.4 – 4.8%
|
14%
|
|
Prothrombin mutation (G20210A)
|
|
|
|
|
|
6.8
|
0.6 – 1%
|
2.6%
|
|
|
26.4
|
2.6 – 3.7%
|
(?)
|
|
Factor V Leiden mutation and prothrombin mutation (G20210A)
|
|
|
|
|
|
50
|
5%
|
(?)
|
|
Protein C deficiency*
|
4.8 – 7.2
|
0.4 – 0.7%
|
1.7%
|
|
Protein S deficiency*
|
3.2
|
0.3 – 0.5%
|
6.6%
|
|
Antithrombin deficiency*
|
4.7 – 64
|
0.4 – 4.1%
|
3.0%
|
In addition to the established genetically determined risk factors for VTEs mentioned
above, a number of other risk factors is described in the literature which may be
associated with an increased risk of thrombosis in pregnancy or which, in the case
of the simultaneous appearance with other thrombophilic risk factors, may modulate
the risk of thrombosis caused by these factors. These include, for example, the homozygous
variants (4G/4G) of the 4G/5G polymorphism of the plasminogen activator inhibitor
type 1 (PAI-1), the increase in the level of plasma coagulation factors, as well as
the increase in lipoprotein (a) and homocysteine. The influence of these not generally
accepted and subordinate risk factors on the risk of thrombosis in pregnancy is not
precisely defined, nor is their interaction with other thrombophilic risk factors.
Thus these factors should generally not be used to estimate the risk of thrombosis
during pregnancy.
Acquired thrombophilia: Antiphospholipid syndrome (APLS)
Among the acquired coagulation disorders, APLS is considered to play a significant
role in the development of thrombotic events during pregnancy [25], [31]. In addition to venous and arterial thromboses, this clinical picture is characterised
by a tendency for spontaneous miscarriages and other pregnancy complications. Antiphospholipid
(APL) antibodies can be detected in affected persons, whereby APL antibodies active
in coagulation (lupus anticoagulants) should be differentiated from those which have
no effect on coagulation tests (in particular cardiolipin antibodies and β2 glycoprotein-I antibodies). The diagnosis of an APLS can then only be made if at
least one of the above clinical signs is present and one or more of the above APL
antibodies can be verifiably detected in a chronological connection; by contrast,
the findings of positive APL antibodies without a clinical correlation do not permit
the diagnosis of an antiphospholipid syndrome, however allow an increased risk of
complications to be suspected. Close management of asymptomatic pregnant women with
increased APL antibodies is therefore recommended.
Older age during pregnancy
The influence of age of the pregnant woman on the risk of thrombosis has been investigated
in numerous studies with results that have not been entirely consistent. Case-control
studies revealed that the relative risk for pregnancy-associated VTEs at an age of
> 35 years is approximately twice as high as at an age of ≤ 35 years [32].
Obesity
Obesity is fundamentally associated with a slight increase in risk for VTEs. For pregnancy-associated
VTEs, a relevant increase in risk has been demonstrated in the case of a body mass
index (BMI) over 30 kg/m2 [9], [33], [34]. In a large population-based cohort study in the United States, pregnant women with
a BMI ≥ 40 kg/m2 (measured before pregnancy) had an adjusted odds ratio for prenatal VTEs of 2.9 (95%
confidence interval 2.2 – 3.8) and for postpartum VTEs of 3.6 (95% confidence interval
2.9 – 4.6), as compared to pregnant women of a normal weight [35]. In view of this finding, the authors of the study consider the significance of
the risk factor of obesity in the current guidelines on VTE prophylaxis in pregnancy,
for example from the ACCP (American College of Chest Physicians) [36], RCOG (Royal College of Obstetricians and Gynaecologists) [32] and ACOG (American College of Obstetricians and Gynecologists) [37] to be only inadequately represented. In the German S3 guideline on VTE prophylaxis
as well, a BMI > 30 kg/m2 is listed only as a risk factor for non-pregnant women and its relative significance
is classified as “moderate” [38].
Caesarean section
Compared to a spontaneous delivery, a Caesarean section is associated with a risk
of postpartum thrombosis which is about twice as high [6], however the absolute risk is still relatively low.
Infertility treatment
Nowadays, women with sterility or (recurrent) miscarriages frequently undergo “fertility
treatments”. A component of these treatments is generally the application of sex hormones
for hormone stimulation. As a result, depending on the nature and dosage of the hormone
administered, an increase in the risk of thrombosis is induced, especially in the
first trimester of pregnancy [39], [40], [41]; this should therefore be taken into consideration clinically. Particularly after
past thrombotic events and/or if clinically relevant thrombophilia is present, conducting
hormone stimulation as part of infertility treatment may possibly be associated with
an increased risk and there should therefore be a careful consideration of the risks
and benefits, because hormone application is formally contraindicated if there is
an existing tendency to develop a thrombosis. For patients at risk, interdisciplinary
management by the infertility centre and a haemostaseological facility is recommended
to precisely assess the risk of thrombosis and, where applicable, develop an optimal
strategy for thrombosis prophylaxis during stimulation and in any subsequent pregnancy
[9], [42].
Predisposing concomitant illnesses
Certain illnesses may be associated with an increase in the risk of thrombosis and
thus also increase the VTE risk in pregnancy and the postpartum period. Cited examples
of this include illnesses that are rheumatic in nature, chronic inflammatory bowel
disease (IBD) such as ulcerative colitis and Crohnʼs disease, as well as infections
[43], [44], [45]. By contrast, uncomplicated varicosis of the lower extremities is associated with
at most a slight increase in the risk of thrombosis in pregnancy.
Surgical procedures and immobilisation
Surgical interventions fundamentally significantly increase the risk of thrombosis
[46], whereby this may be increased even further by postoperative immobility or complications
within the scope of the procedure (e.g. infection). Immobility during pregnancy and
the postpartum period also represents a risk factor for VTEs, independent of an intervention.
Where applicable, the risk of thrombosis during pregnancy must therefore be evaluated
differently if there is immobilisation in addition to an existing predisposition to
thrombotic events.
Estimation of the Thrombotic Risk in Pregnancy
Estimation of the Thrombotic Risk in Pregnancy
To clarify the need for medical thrombosis prophylaxis during pregnancy, an estimation
of the risk of thrombosis is necessary. For this purpose, all known predispositional
and expositional risk factors of the pregnant woman must be taken into account [9], [32], [36], [47], [48], [49], [50], [51].
The rationale for conducting medical thrombosis prophylaxis in pregnancy is that the
prothrombotic shift of the haemostatic balance, together with predispositional and
expositional risk factors, can lead to an imaginary “critical threshold” being exceeded
which then leads to the manifestation of thrombotic events ([Fig. 1]). Special risk scores for pregnant women have been developed based on this concept
[32], [52]. For this purpose, a sum score is formed from the available individual factors weighted
according to their prothrombotic relevance and this score provides information on
the level of the overall risk of the pregnant woman for VTEs. Such scores can be very
helpful for making a decision for or against medical thrombosis prophylaxis or for
referring the patient to a haemostaseologist.
Fig. 1 Summary of the individual risk of thrombosis during pregnancy. If the total risk
exceeds an imaginary “critical threshold” (dashed line), there is a manifestation
of the thrombotic event.
The significance of any hereditary and/or acquired thrombophilic risk factors for
the risk of thrombosis in pregnancy should once again be stressed here. Diagnostic
measures for thrombophilia should then be performed if there is already a particular
predisposition of the pregnant woman for thrombotic events and if consequences with
regard to medical thrombosis prophylaxis would arise from the additional detection
of thrombophilia. It is important that diagnostic measures for thrombophilia be performed
during the planning phase of a pregnancy, among others, if the woman has a positive
family history with regard to thrombotic events. The positive family history in combination
with thrombophilia may represent an indication for medical thrombosis prophylaxis
in pregnancy and the postpartum period.
Drugs for the Treatment and Prophylaxis of Thrombotic Events in Pregnancy
Drugs for the Treatment and Prophylaxis of Thrombotic Events in Pregnancy
Low-molecular-weight heparins
Low-molecular-weight heparins (LMWH) represent the standard medication for the prophylaxis
and treatment of thrombotic events within the scope of pregnancy and the postpartum
period [9], [32], [36], [38], [53], [54], [55], [56], [57], [58], [59], [60], [61] and have by now largely replaced the unfractionated heparins (UFH) formerly used.
In comparison to UFH, LMWHs are characterised in particular by the more favourable
adverse effect profile (better tolerability, low risk for heparin-induced thrombocytopaenia
[HIT]) with at least comparable efficacy. An overview of the currently available heparins
and the pentasaccharide fondaparinux is shown in [Table 3].
Table 3 Overview of parenteral anticoagulants for pregnancy.
|
Anticoagulant
|
Mean molecular weight (Dalton)
|
Ratio of anti-Xa and anti-IIa effect
|
Method of production
|
|
Unfractionated heparin (UFH)
|
5 000 – 30 000
|
1
|
–
|
|
Dalteparin
|
6 000
|
2.5
|
Hydrolysis with HNO2
|
|
Certoparin
|
5 200
|
2.2
|
Hydrolysis with isoamyl nitrite
|
|
Nadroparin
|
4 500
|
2.5 – 4
|
Hydrolysis with HNO2 and fractionation
|
|
Enoxaparin
|
4 500
|
3.6
|
Benzylation and alkaline β-elimination
|
|
Reviparin
|
4 150
|
3.6 – 6.1
|
Hydrolysis with HNO2
|
|
Tinzaparin
|
6 500
|
1.5 – 2.5
|
Enzymatic β-elimination
|
|
Fondaparinux
|
1 728
|
Only anti-Xa effect
|
Artificial chemical synthesis
|
For the primary and secondary prophylaxis of VTE, LMWHs are used during pregnancy generally at a dosage adapted to the high-risk
prophylaxis. Various LMWHs which are available as a pre-filled syringe for self-application
by the patients are available for this. Recently, tinzaparin received German approval
for high-risk prophylaxis at a dosage of 4,500 IU/d and is now also available as a
pre-filled syringe for VTE prophylaxis in pregnancy; according to the summary of product
characteristics, there are data in more than 2,000 cases available on the use of tinzaparin
in pregnancy.
LMWHs at a therapeutic dosage are used for the treatment of thrombotic events in pregnancy. In this connection, therapeutic anticoagulation
with a once-daily heparin application is possible with tinzaparin, while other LMWHs
must be applied twice daily in therapeutic use.
An overview of the standard dosages of LMWHs for the prophylaxis and treatment of
pregnancy-associated VTE is presented in [Table 4]; it should be emphasised that in justified cases, there may have to be deviations
from these standard dosages.
Table 4 Dosage of low-molecular-weight heparins (LMWH) and fondaparinux for the prophylaxis
and treatment of thrombotic events in pregnancy.
|
Substance group
|
Active substance
|
Preparation
|
Dosage
|
|
Prophylaxis
|
Therapy
|
|
BW = Body weight
|
|
Low-molecular-weight heparin (LMWH)
|
Certoparin
|
Mono-Embolex® (Aspen)
|
1 × 3000 IU/d s. c.
|
2 × daily 8,000 IU s. c. (Independent of BW)
|
|
Dalteparin
|
Fragmin® (Pfizer)
|
1 × 5000 IU/d s. c.
|
2 × daily 100 IU/kgBW s. c.
|
|
1 × daily 200 IU/kgBW s. c.
|
|
Enoxaparin
|
Clexane® (Sanofi)
|
1 × 40 mg/d s. c.
|
2 × daily 1 mg/kgBW s. c.
|
|
Nadroparin
|
Fraxiparin® (Aspen)
|
1 × 0.3 ml/d s. c.
|
2 × daily 0.1 ml/10 kgBW s. c.
|
|
Tinzaparin
|
Innohep® (LEO Pharma)
|
1 × 4500 IU/d s. c.
|
1 × daily 175 IU/kgBW s. c.
|
|
Pentasaccharide
|
Fondaparinux
|
Arixtra® (Aspen)
|
1 × 2.5 mg/d s. c.
|
< 50 kgBW: 1 × daily 5 mg s. c.
50 – 100 kgBW: 1 × daily 7.5 mg s. c.
> 100 kgBW: 1 × daily 10 mg s. c.
|
Fondaparinux
The pentasaccharide fondaparinux represents an alternative to the prophylaxis and
treatment of VTEs in pregnancy [62], [63], [65]. The preparation is characterised by good tolerability and a low rate of allergic
reactions. However, in contrast to LMWH, fondaparinux crosses the placental barrier.
This crossing of the placental barrier is indeed generally considered to be nonproblematic;
nonetheless, the use of fondaparinux in pregnancy should be limited to those cases
in which LMWH cannot be used [32], [36], [55], such as in the case of HIT and intolerance to (various) LMWHs, particularly cutaneous
allergic reactions.
Danaparoid
The heparinoid danaparoid principally also represents an alternative for the prophylaxis
and treatment of thrombotic events if LMWH cannot be used after previous HIT or allergic
reactions to the application of LMWH. Nowadays, danaparoid is still used only very
rarely during pregnancy [66], [67].
Oral anticoagulants
Vitamin K antagonists (VKA), in particular phenprocoumon and warfarin, cross the placental
barrier; when they are used during pregnancy, particularly during the first trimester,
embryotoxic effects have been described (so-called “warfarin embryopathy”) [68]. As a result, its use is prohibited, particularly in the phase which is crucial
for embryonic development, the first trimester of pregnancy. In rare exceptional cases,
particularly in women with a mechanical heart valve replacement, VKA are used after
the first trimester for prophylaxis of thrombotic complications.
Experiences with non-vitamin-K-dependent oral anticoagulants (NOAK), the direct oral
thrombin inhibitor (DTI) dabigatran etexilate and the oral Xa inhibitors rivaroxaban,
apixaban and edoxaban during pregnancy are limited. These anticoagulants are not formally
approved during pregnancy and breastfeeding. However, the few reports available indicate
that, if NOAKs are inadvertently used in the first trimester of pregnancy, there are
apparently not more frequent maternal complications or damage to the embryo; the use
of NOAKs in early pregnancy therefore does not represent a sufficient justification
for discontinuation of a pregnancy, according to current circumstances.
If a pregnancy occurs during exposure to VKAs or NOAKs, the oral anticoagulation must
be stopped and a rapid switch made to a parenteral anticoagulant, generally an LMWH
[9].
It is important to note that the VKA phenprocoumon as well as NOAKs should not be
used during breastfeeding. If oral anticoagulation is necessary during breastfeeding,
the VKA coumadin, which does not pass into breast milk, can be used for this purpose.
Alternatively, parenteral anticoagulation can of course be performed with an LMWH
or fondaparinux during breastfeeding [9].
Laboratory Testing on Antithrombotic Medication in Pregnancy
Laboratory Testing on Antithrombotic Medication in Pregnancy
Concomitant laboratory monitoring during medical prophylaxis or treatment of VTE during
pregnancy is the subject of controversial discussion. From the authorʼs viewpoint,
periodic laboratory checks are advisable for various reasons [9].
A dreaded adverse effect of the application of heparins is HIT which is a serious
thrombotic condition. In comparison to the use of UFH, the risk of HIT in the case
of LMWH is extremely low; in addition, this complication occurs predominantly in at-risk
surgical patient collectives (e.g. in vascular surgery) and is quite rare in the conservative
specialty, particularly in pregnancy. Consequently, routine blood count testing during
heparinisation in pregnancy and the postpartum period for early detection of HIT,
where applicable, is no longer recommended nowadays. If thrombocytopaenia occurs in
pregnancy during heparinisation, a causal HIT should be considered as a differential
diagnosis; however, gestational thrombocytopaenia and immunothrombocytopaenia represent
by far the most common causes of thrombocytopaenia during pregnancy.
Since the anticoagulatory heparin effect is not constant throughout pregnancy due
to the physiological changes of haemostasis, an anticoagulation dose increase may
be necessary. The effect of the parenteral anticoagulants used (LMWH, fondaparinux,
danaparoid) can be observed by determining the anti-factor-Xa activity, whereby the
method should be calibrated to the anticoagulant used. To document the crucial peak
levels of the anticoagulants used for assessing the dosage, the blood samples should
be taken, where applicable, about 3 – 4 hours after the last injection of the anticoagulant.
Along with the anti-factor-Xa activity, other criteria for dose adjustment of the
parenteral anticoagulants during pregnancy can be used: Unusually high activation
markers (such as D-dimers) may indicate insufficient coagulation inhibition and require
an increase in the dosage.
Finally, it should be noted that, for the parenteral anticoagulants used, in particular
LMWH, there is indeed much experience on use during pregnancy and breastfeeding, but
these are not formally approved for use in pregnancy. Thus they should be used following
a careful benefit/risk consideration and suitable monitoring should be performed to
detect any potential toxicity. There may be hepatotoxic adverse effects with an increase
in liver values during parenteral anticoagulation and this may necessitate a switch
in the anticoagulation. Since renal failure may result in a restriction regarding
the use of parenteral anticoagulants or may necessitate a dose reduction, it is additionally
recommended to check renal function – particularly in the case of therapeutic anticoagulation
or patients at risk. The potential for accumulation of long-chain LMWHs, such as tinzaparin
and dalteparin, is the lowest if there is renal dysfunction because of an alternative
elimination pathway via the reticuloendothelial system (RES) [62].
Medical Thrombosis Prophylaxis in Pregnancy and the Postpartum Period
Medical Thrombosis Prophylaxis in Pregnancy and the Postpartum Period
As is also the case outside of pregnancy, the avoidance of immobility is the crucial
basic measure for preventing pregnancy-associated VTEs. After delivery, early mobilisation should
be ensured and this can also be supported through physical therapy, where applicable
[9]. With regard to an indication for medical thrombosis prophylaxis, a distinction
should be made between situational transient thrombosis prophylaxis, primary and secondary
prophylaxis [9], [47], [48], [49], [50], [51].
Transient/situational prophylaxis
Thrombosis prophylaxis during pregnancy for a limited period of time is administered
due to transient, situational risk factors or risk situations which are associated
with an increased risk of thrombosis in the pregnant woman. These include surgical
interventions, immobilisation, serious infections and long-distance (air) travel with
travel lasting more than 3 – 4 hours. In such situations, there is already an increased
risk of thrombosis, which is increased even further during pregnancy. Fundamentally,
in all cases in which transient medical thrombosis prophylaxis is also administered
outside of pregnancy, corresponding prophylaxis should be conducted during pregnancy;
this can be implemented according to the corresponding guideline recommendations [38].
Primary prophylaxis
To be able to adequately determine an indication for medical thrombosis prophylaxis
in pregnancy, an individual consideration of the risk of thrombosis of the pregnant
woman is necessary, taking into account all known predispositional and expositional risk factors. Here, the presence of hereditary thrombophilic risk factors is also
of particular significance, especially factor V Leiden mutation (factor V G1691A),
prothrombin mutation (factor II G20210A) as well as protein C, protein S and antithrombin
deficiency.
Determining the absolute risk of thrombosis in pregnancy given the presence of genetically
determined thrombophilia is not without problems, since the presence of other predispositional
risk factors must be incorporated into the determination of overall risk. At the same
time, various thrombophilic risk factors may be present which can then increase the
thrombotic risk – possibly beyond multiplicatively. Thus, for example, the heterozygous factor V Leiden mutation in
the case of a lack of predisposition otherwise is associated with a risk of thrombosis
of approx. 0.3% in pregnancy [10], [23]; therefore this mutation alone is not an indication for primary medical prophylaxis
during pregnancy. By contrast, the homozygous factor V Leiden mutation with a risk
of thrombosis of approx. 1.5% and the combination of heterozygous factor V Leiden
and heterozygous prothrombin mutation with a risk of approx. 5% in pregnancy [10], [23] generally justifies medical prophylaxis during pregnancy, even if no other predisposing
risk factors are present. The fact that the absolute risks indicated can still greatly
increase if other predispositional risk factors for VTE are present must be taken
into account. For example, the positive family history for VTE leads to an increase
in risk which is about 2 – 4 times as high, the obesity doubles to triples the risk
of thrombosis, and in the case of older age during pregnancy, the risk of thrombosis
also increases.
While medical primary prophylaxis in pregnancy and the postpartum period per se is
generally not necessary in the case of a minor predisposition for thrombotic events
(such as a BMI of 25 – 30 kg/m2), primary medical thrombosis prophylaxis is recommended during the postpartum period
in the case of a moderate predisposition – generally in the case of a combination
of mild thrombophilia with another predispositional risk factor. If additional risk
factors which promote the risk of thrombosis occur during pregnancy, medical thrombosis
prophylaxis is already initiated in pregnancy, where applicable. If there is a severe
predisposition for thrombotic events, such as severe thrombophilia, medical thrombosis
prophylaxis is given throughout the entire pregnancy. As a general principle, medical
thrombosis prophylaxis started during pregnancy is generally continued for about six
weeks following delivery due to the risk of thrombosis which peaks during the postpartum
period. If epidural anaesthesia (EA) or a Caesarean section is performed during delivery,
there should be a period of at least 12 hours between the last heparin administration
and the implementation of the intervention or delivery [9], [32].
A general algorithm ([Fig. 2]) as well as an algorithm if thrombophilia is present ([Fig. 3]) for primary medical prophylaxis during pregnancy are represented graphically.
Fig. 2 Primary prophylaxis of thrombotic events during pregnancy with the presence of predispositional
risk factors.
Fig. 3 Primary prophylaxis of thrombotic events during pregnancy with the presence of thrombophilia.
* Depending on the nature and severity of the inhibitor deficiency. ** Deep venous
thrombosis, particularly in first-degree relatives. *** Depending on the nature and
severity of the risk factor; where applicable, repeated examination in pregnancy is
necessary. **** In the case of medical thrombosis prophylaxis conducted during pregnancy,
this is also generally continued over 6 weeks post partum.
Secondary prophylaxis
In patients with a history of VTE which occurred prior to pregnancy, there is an increased risk of recurrence during pregnancy which may
be 10 – 20%, depending on the existing constellation. Therefore these women generally
receive medical thrombosis prophylaxis, particularly after events occurring spontaneously
or events with a hormonal trigger (on hormonal contraception, hormone [replacement]
therapy [HRT] or in an earlier pregnancy). In the case of patients with a significant
transient risk factor, such as after severe trauma or a major surgical procedure,
waiting may be justified. Since the risk of thrombosis and also the risk of recurrence
after a prior event are elevated from the start of the pregnancy, medical thrombosis
prophylaxis is begun promptly when pregnancy occurs and generally continued for 6
weeks post partum; if situational risk factors last more than 6 weeks after delivery,
the medical thrombosis prophylaxis may need to be prolonged further [47], [48], [49], [50], [51]. In the case of therapeutic heparinisation, there should be at least 24 hours between
the last heparin administration and delivery – particularly if epidural anaesthesia
is administered [32]. Failure to observe this interval can significantly increase the risk of bleeding
complications, particularly within the scope of the epidural anaesthesia. If there
is a high risk of thrombosis, UFH can be given intravenously up to 4 – 6 hours before
the intervention; if the corresponding interval cannot be observed, performing epidural
anaesthesia should be avoided, if applicable [9], [69].
An algorithm for medical secondary prophylaxis in pregnancy following prior thrombotic
events is shown in [Fig. 4].
Fig. 4 Secondary prophylaxis following a prior VTE in pregnancy. * In particular hormonally
triggered events (on hormonal contraception, hormone (replacement) therapy [HRT] or
in earlier pregnancy). ** Where applicable, repeated review of acquired/expositional
risk factors during pregnancy necessary.
Anticoagulation in the Case of Thrombotic Events in Pregnancy
Anticoagulation in the Case of Thrombotic Events in Pregnancy
If a deep venous thrombosis occurs during pregnancy with or without a concomitant
pulmonary embolism, therapeutic anticoagulation is necessary; this is generally conducted
using a LMWH at a therapeutic dosage and in exceptional cases using fondaparinux at
a therapeutic dosage [47], [48], [49], [50], [51]. A dose reduction does not take place for the duration of the anticoagulation if
no special circumstances – such as increased bleeding tendency – are present under
anticoagulation [9].
As a general principle, the anticoagulation is administered for at least 3 months
and is always continued for a period of 6 weeks post partum since the thrombotic risk
“peaks” during the postpartum period. In the postpartum period, the anticoagulation
can be administered either parenterally or a switch to an oral form can be made. However,
it should be borne in mind that all currently available NOAKs are contraindicated
during breastfeeding and that the VKA phenprocoumon, which is predominantly used in
Germany, passes into breast milk and can induce or worsen a vitamin K deficiency in
the newborn. Therefore only warfarin – which does not pass into breast milk and which
is therefore also approved for use during breastfeeding – is currently considered
for oral anticoagulation during breastfeeding. The switch to warfarin must be started
such that it overlaps the parenteral anticoagulation, where applicable; the latter
can be stopped if the INR value on warfarin is in the desired target range after loading
(generally 2.0 – 3.0). If permanent anticoagulation is required in women with repeat
VTEs, this can be switched to an oral form before the end of breastfeeding or in the
case of women who are not breastfeeding, whereby alternatively a NOAK (the Xa inhibitors
rivaroxaban, apixaban and edoxaban as well as the direct oral thrombin inhibitor [DTI]
dabigatran etexilate are currently available) or a VKA, generally phenprocoumon, can
then be used [9].
An algorithm for anticoagulation in pregnancy-associated thrombotic events is shown
in [Fig. 5].
Fig. 5 Anticoagulation in the appearance of thrombotic or thromboembolic events during pregnancy.
Following pregnancy-associated thrombotic events, no long-term or permanent anticoagulation
is generally necessary, as in the case of other thrombotic events in a defined risk
situation. However, there may be deviations from this if there is a marked predisposition
for thrombotic events or a significantly increased future risk of recurrence is assumed;
this may be the case, for example, if there is severe thrombophilia or in the case
of recurrent thrombotic events. To clarify this question, it is recommended in corresponding
cases that affected patients present to an outpatient coagulation unit.
Even if there is no permanent anticoagulation following pregnancy-associated VTEs,
the following consequences result [9]:
-
Taking hormonal contraceptives should preferably be avoided following pregnancy-associated
and other hormonally triggered events; where applicable, a pure gestagen preparation
(“minipill”) can be used for contraception. However, in doing so, formal legal reasons
should be observed since according to the summary of product characteristics, “minipills”
are also contraindicated following VTEs.
-
In risk situations following pregnancy-associated events, medical thrombosis prophylaxis,
generally with a LMWH, should be given, where applicable.
-
According to the guideline, medical thrombosis prophylaxis, generally with LMWH, is
indicated in a subsequent pregnancy from the start of the pregnancy until (at least)
6 weeks post partum, following a previous pregnancy-associated event in a previous
pregnancy.
